The most common etiology of infection-related death or neurodevelopmental impairment in neonates with birth weight less than 750 grams is invasive candidiasis. Invasive candidiasis is diagnosed by positive culture for Candida species from normally sterile body fluid. Over 70% of the premature infants who develop invasive candidiasis will die or suffer severe, permanent neurologic impairment. The highest-risk infants are the very young: the cumulative incidence in neonates with birth weight of less than 750 grams is 16%, and most of these infants experience infection by day of life 49. It has been shown that invasive candidiasis is safely prevented by administering fluconazole prophylaxis in immunocompromised adults. Fluconazole has been commonly used off-label in the neonatal intensive care unit, but definitive recommendations for its use in the nursery have been hampered by the limited number of well-designed trials. In neonates weighing less than 750 grams, appropriate dosing is not known, definitive safety and long-term follow up trials have not been completed, and there have not been well-powered trials conducted to establish the efficacy of the product using mortality as part of the primary endpoint. Three recent proof-of-concept studies suggest that fluconazole will be safe and effective, and an ongoing pharmacokinetic study is providing data to give preliminary dosing guidance. The next logical step in drug development is proposed by this research: to conduct a pivotal trial to determine the safety and efficacy of fluconazole in premature infants with 2-year neurodevelopmental follow-up assessment. This will be accomplished by randomizing 360 infants, with a birth weight less than 750 grams, at 20 centers, to fluconazole or placebo. The primary efficacy endpoint will be Candida-free survival at study day 49. The research will establish definitive dosing, safety, and efficacy of fluconazole;it will also provide critical information on the effects of fluconazole on neurodevelopmental impairment and antifungal resistance. This research will evaluate whether fluconazole decreases invasive infection from Candida in neonates less than 750 grams birth weight. The research will evaluate the efficacy, safety, and neurodevelopmental outcomes related to fluconazole use.